2-Minute Consultation: Fatigue as a Side Effect

FEBRUARY 01, 2009

Jeannette Y. Wick, RPh, MBA, FASCP

Ms. Wick is a senior clinical research
pharmacist at the National Cancer
Institute, National Institutes of Health,
Bethesda, Maryland. The views expressed
are those of the author and not those of
any government agency

Americans have a propensity to
wear themselves out with their
never-ending activity, multitasking,
and ignoring their hardwired need for
rest. The exhaustion continuum begins
with simply being tired, progresses
through periods that might be described
as weary or worn out; can include indifference
or apathy; and ends at overwhelming
fatigue.1 Like pain, fatigue is
an objective and subjective state. When
physical overexertion is the cause, fatigue
is the extreme and expected end point.
This type of fatigue occurs in otherwise
mentally and physically healthy people
when they eat poorly, exercise too much,
and/or skimp on rest.2

Pathologic fatigue is decreased capacity
for physical or mental work disproportionate
to changes in activity or
stimuli and unresolved by bed rest. If
it occurs daily or almost daily for 2
weeks, fatigue becomes a serious problem.1,3,4
Fatigue is normally distributed
in the population; so for each individual
who reports fatigue, another fortunate
individual reports boundless energy.5-7
Fatigue—an absence of energy—can
make patients feel physically weak,
mentally dull, or both (Table). Any
effort exhausts fatigued patients quickly,
and fatigue has physical, mental, and
emotional components.

Acute (lasting <6 months) or chronic
(lasting >6 months)4 fatigue troubles
patients and confounds and frustrates
physicians with its vague presentation.
10-12 Fatigue is the precipitating complaint
for more visits to primary care
physicians than colds, rashes, headache,
or chest pain. Chronic fatigue can be
disabling.

Numerous underlying conditions,
especially
cancer or HIV infection and
their treatments, have been associated
with fatigue. Also among the most common
causes are bacterial and viral infections,
arthritis, sleep disorders, anxiety,
depression,
chronic fatigue syndrome,
fibromyalgia, cardiovascular disease,
multiple sclerosis (MS), and lung disease.
Patients also report causes unrelated to
disease: overexertion, isolation, medication
side effects, and paradoxically,
boredom.13

How Common Is Fatigue?

Measuring fatigue's prevalence is a significant
challenge due to its mercurial
definitions. Determining how many
people experience fatigue—and when
it becomes abnormal—is an imprecise
science. Simple validated tools are rare
and cannot be used in all populations.3
Most come from clinical trials and can
be difficult or time-consuming to use.1
Thus, an exact prevalence is unknown.

To assess fatigue, clinicians often ask
these questions and prompt patients to
provide additional information:

Are you experiencing fatigue?

On a scale of 1 to 10, where 1 is no
fatigue and 10 is fatigue so severe
you cannot function, what is your
average fatigue level in the last 2
weeks?

How does fatigue interfere with
your ability to function?1

As they listen, clinicians should try
to identify temporal patterns of onset,
course, and duration; exacerbating and
relieving factors; and specific distress
associated with the fatigue. Sometimes
asking patients, "Do you have any ideas
about what caused this?" cuts to the
chase. A fourth question, "Do bed rest or
vacations alleviate the fatigue?" is helpful.
Conducting a medication review is
often illuminating.14,15

Medications and Fatigue

Numerous medications are associated
with fatigue. Sometimes, as with hydrochlorothiazide
combination products,
an interaction magnifies the fatigue.

Table

Fatigue Signs and Symptoms

Treatment is, by necessity, empiric.
After correcting any underlying problems
that may cause or contribute to
the fatigue, some clinicians will wait
for a change in the patient's condition.
This approach tends to distance and
disappoint patients, however.4 A more
aggressive approach combines available
interventions. Clinicians must start
with a careful discussion about what to
expect, including:

Reconciling patients' hopes with
reasonable expectations14

Advising patients that fatigue can be managed, but treatment
or cure is unlikely14

Reducing patients' anxiety and stress by describing what
they can honestly expect, drawing from clinical evidence
and experience16,17

When a medication or a combination of medications is
the cause and they cannot be eliminated, clinicians should
consider:

Tapering to the lowest effective dose is prudent.

Dosing so that the most profound period of fatigue, if
it is predictable, occurs during the night, can minimize
fatigue's impact.

Using less sedating alternatives (eg, lamotrigine instead
of carbamazepine)
may help.

Adding new medications to the patient's regimen only if
they are absolutely necessary.

Determining if depression is a factor, and treating it with
nonsedating agents may improve the fatigue.

Clinicians' Role

For all causes of fatigue, the health care team should promote
active management strategies, like improved diet, more exercise,
and better control of patients' underlying disease states.
Increased aerobic activity, beginning with light exercise of
short duration and increasing as tolerated, is essential unless
it is clearly contraindicated.8 Patients with fatigue also need
adequate sleep and good nutrition.6 Passive management
strategies (sleeping through the fatigue period, limiting activities,
or pushing through with activities despite fatigue) do not
lead to improvement.

At the very least, clinicians should try to help patients identify
the time of day when energy peaks and have them plan
around that time and pace themselves; many elderly people
learn to do this intuitively.4,6 Getting adequate sleep is essential,
and napping can be very helpful. Some patients benefit
from reviewing their normal activities and identifying ways
to conserve energy.

If fatigue is profound and the agent causing it cannot be
discontinued, clinicians might consider prescribing methylphenidate
or modafinil to increase alertness and energy.
Amantadine also has been used to treat fatigue associated
with MS, with mixed results.18-20

Pharmacists should be aware that patients may look to
complementary or alternative medicines, especially coenzyme
Q, cordyceps mushrooms, dehydroepiandrosterone,
dong quai, evening primrose oil, ginseng, maitake, rhodiola,
and vitamin B12. Pharmacists should stress to patients that
many of these are eliminated via the liver, and large doses
may harm the liver. They also may interact with prescription
drugs, and their use for fatigue is rarely supported by studies.9
Patients should ask their prescribers or pharmacists before
taking these agents.

Table

Medications that Can Cause Fatigue

Agent or Class

Fatigue Potential

Suggested Mechanisms Behind Fatigue

ACE inhibitors

Moderate

Alfuzosin

Moderate

Amlodipine

Moderate

Anticonvulsants

Very high

Antineoplastic agents

Very high

Cancer itself has been associated with profound fatigue

Antiretrovirals

Moderate

Fatigue among HIV-infected patients may be due to hepatic decline, coinfection, anemia, increased cytokine levels, adrenal insufficiency, depression, anxiety, and a host of other comorbid conditions

Beta-blockers

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Buspirone

Moderate

Carvedilol

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Clonidine

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Corticosteroids

Moderate

May alter diurnal rhythm and cause sleep disturbances

Disease-modifying drugs

High

Immune system dysregulation may increase cytokine levels and lead to fatigue

Dopaminergic agents

Very high

Duloxetine

High

Famciclovir

Moderate

Guanfacine

Very high

Hydrochlorothiazide/metoprolol

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Hydrochlorothiazide/irbesartan

High

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue